Metabolic disorders comprise a collection of health disorders or risks that increase the risk of morbidity and loss of qualify of life. For example, diabetes, obesity, including central obesity (disproportionate fat tissue in and around the abdomen), atherogenic dyslipidemia (including a family of blood fat disorders, e.g., high triglycerides, low HDL cholesterol, and high LDL cholesterol that can foster plaque buildups in the vascular system, including artery walls), high blood pressure (130/85 mmHg or higher), insulin resistance or glucose intolerance (the inability to properly use insulin or blood sugar), a chronic prothrombotic state (e.g., characterized by high fibrinogen or plasminogen activator inhibitor-1 levels in the blood), and a chronic proinflammatory state (e.g., characterized by higher than normal levels of high-sensitivity C-reactive protein in the blood), are all metabolic disorders collectively afflicting greater than 50 million people in the United States.
PGC1α (PPARγ coactivator-1α) is a transcriptional coactivator that mediates many biological programs related to energy metabolism. Originally described as a coactivator of PPARγ that modulated expression of uncoupling protein 1 (UCP1) and thermogenesis in brown fat, it has also been shown to control mitochondrial biogenesis and oxidative metabolism in many cell types. PGC1α is induced in muscle by exercise and stimulates many of the known beneficial effects of exercise in muscle: mitochondrial biogenesis, angiogenesis and fiber-type switching (Handschin and Spiegelman (2008) Nature 454, 463-469). It also provides resistance to muscular dystrophy and denervation-linked muscular atrophy (Sandri et al. (2006) Proc. Natl. Acad. Sci. USA 103, 16260-16265). The healthful benefits of elevated muscle expression of PGC1α may go beyond the muscle tissue itself. Transgenic mice with mildly elevated muscle PGC1α are dramatically resistant to age-related obesity and diabetes and have a prolonged life-span (Wenz et al. (2009) Proc. Natl. Acad. Sci. USA 106, 20405-20410), which suggests that PGC1α might stimulate the secretion of factors from skeletal muscle that affects the health and function of other tissues.
Despite decades of scientific research, such factors have not been identified and few effective therapies have emerged to treat metabolic disorders and related cardiovascular disease (cardiovascular disease remains the main cause of mortality in the Western world). Accordingly, there is a great need to identify molecular regulators of metabolic disorders, including the generation of diagnostic, prognostic, and therapeutic agents to effectively control metabolic disorders in subjects.